Prostate cancer is currently the most common type of cancer in American men and the second leading cause of cancer related death in this population. In its advanced stages, prostate cancer metastasizes preferentially to bone, where it forms osteoblastic lesions. After initial treatment with androgen ablation therapy, most metastatic prostate cancers become hormone-refractory and lethal. The major cause of morbidity and mortality from prostate cancer is advanced stage, androgen independent disease.
There is currently no effective therapy for hormone refractory prostate cancer and there is currently no marker specific for hormone refractory prostate cancer. In addition to an urgent need for new therapies, there is also a need for diagnostic tests of hormone refractory-prostate cancer. Such tests would indicate which patients have hormone refractory cancer cells at diagnosis and where they are located. This information would have a profound impact on initial therapy. In addition, markers of hormone independent prostate cancer could be used to detect recurrent disease and could be used as therapeutic targets.
Despite recent advances in the diagnosis and treatment of localized prostate cancer, little progress has been made in the fight against advanced disease. Virtually all patients treated with hormone ablation therapy will go on to develop androgen independent recurrences, for which there currently is no therapy. Knowledge of the specific molecular events underlying the progression of prostate cancer to androgen independence is limited.
An understanding of the mechanism of androgen independent growth would provide the framework for the development of rational therapies. The development of specific markers of androgen independent growth would lead to the early identification of patients at risk to fail surgical or hormonal therapy and to the selection of patients for alternative therapies. A number of hypotheses have been advanced to explain the biological basis of androgen independence.
One hypothesis is that androgen independence arises through alterations in the androgen receptor. These alterations include overexpression of the androgen receptor, amplification, or mutation (Kokontis et al., 1994; Visakorpi et al., 1995). Taplin et al. recently demonstrated androgen receptor mutations in 50% of patients with hormone refractory disease (Taplin et al., 1995). Mutated receptors have been demonstrated to respond to ligands other than testosterone, including estrogen, insulin growth factor, the androgen antagonist flutamide, and keratinocyte growth factor (Culig et al., 1994; Scher and Kelly, 1993).
Although androgen receptor mutations may contribute to androgen independence, evidence supports the existence of alternative mechanisms. The prostate cancer cell line LNCaP maintains its androgen dependence despite an androgen receptor mutation that renders it sensitive to estrogen (Culig et al., 1994; Veldsholte et al., 1990). Similarly, in androgen receptor negative, androgen independent cell lines such as PC3, introduction of functional androgen receptor does not restore androgen sensitivity, suggesting that androgen receptor is not all that is necessary for androgen sensitivity (Krongrad et al., 1991; Yuan et al., 1993).
Other mechanisms of androgen independence have been proposed. BcL-2 overexpression correlates with hormone resistance, and hyperexpression of bcl-2 in LNCaP prostate cancer cells can confer androgen independence in vivo (McDonnell et al., 1992; Raffo et al., 1995). p53 mutation, c-myc overexpression and protein kinase C activation have also been associated with advanced prostate cancer and hormone resistance in some patients and cell lines (Bookstein et al., 1993; Kokontis et al., 1994; Krongrad and Bai, 1994; Raffo et al., 1995).
The mechanisms by which bcl-2, c-myc and other genes mediate androgen resistance are not known. One hypothesis is that androgen independence represents an arrested stage of stem cell development. Supporting this hypothesis is the finding that c-met and bcl-2 expression is restricted to the basal epithelium of normal prostate, which contains the androgen independent prostatic stem cell population (Bonkhoff and Remberger, 1996; Bonkhoff et al., 1994; Pisters et al., 1995). A gene disclosed herein, E25a, also is expressed in basal epithelium of normal prostate, supporting this hypothesis. Androgen independence, therefore, may result from upregulation of stem cell genes that promote immortalization and/or self renewal.